SUMMARY: The overarching goal of this Program Project Grant (PPG), entitled ?Comparative Genomics of Longevity,? is to identify molecular mechanisms responsible for health and longevity, with the focus on genome/epigenome stability in long-lived rodent species, and then develop strategies to adapt these mechanisms to benefit human health. Rodents are an ideal group for comparative aging studies because they are phylogenetically related, even though their lifespans are extremely diverse, ranging from 2-4 years in mice and rats to over 20 years in naked mole rats, beavers, porcupines, and squirrels. Characterization of the processes responsible for this disparity in lifespan may enable the development of interventions in the aging process to prevent, delay or cure age-related diseases. The central hypothesis of this PPG, therefore, is that long-lived species have evolved more efficient mechanisms to maintain genome/epigenome stability and prevent age-related diseases, which can be adapted to extend the healthspan of other species. In the first phase of the PPG, we generated exciting data that support our central hypothesis. Specifically, we identified DNA double strand break repair as a mechanism that strongly correlates with longevity; we were able to improve DNA repair in mouse cells by introducing specific amino acid changes from the beaver; we showed that the naked mole rat hyaluronan synthase 2 gene improved mouse health; we obtained evidence that mutation rates are higher in short-lived species, we developed a model that reports the biological age of mice, and we identified multiple omics profiles characteristic of long-lived species. This PPG is comprised of four highly integrated projects and three cores. Project 1 (Vera Gorbunova) is focused on mechanisms responsible for more efficient genome/epigenome stability in long-lived species. Project 2 (Andrei Seluanov) studies mechanisms responsible for longevity and cancer-resistance of the longest-lived rodent, the naked mole rat. Project 3 (Jan Vijg) investigates whether long-lived species have lower frequencies of mutations and epimutations using novel, high throughput single-cell approaches. Project 4 (Vadim Gladyshev) uses omics approaches to identify genes and pathways involved in genome and epigenome stability that are differentially regulated in long-lived species. The research team consists of five investigators dedicated to longevity research who are experts in comparative biology and DNA repair (Gorbunova), cancer-resistance and long-lived rodents (Seluanov), mutagenesis and high throughput, single-cell approaches (Vijg), comparative genomics (Gladyshev), and bioinformatics (Zhang, Core C). Moreover, the team has developed a collection of primary rodent cells and tissues, and naked mole rat colonies, specifically to facilitate comparative studies of longevity (Seluanov, Core B). This assembly of expertise allows unprecedented insight into the biology of longevity. This team of investigators is uniquely positioned to pursue studies of longevity across species using a combination of cell, molecular, and genomic approaches.